The diagnosis of most upper GI tract conditions is currently accomplished by upper endoscopy with biopsy (EGD). EGD is costly primarily because it requires conscious sedation, necessitating that procedures be conducted by physicians in a specialized endoscopy suite, and that patients take time away from work and family. Another limitation is sampling error - endoscopic biopsies are frequently random, resulting in many instances of missed disease. Methods such as unsedated transnasal endoscopy (uTNE) have been proposed to decrease the cost of EGD. While in principle uTNE techniques could be used in most cases, physician- associated expense, poor patient acceptance, and an inability to obtain adequate biopsies have hampered its adoption. As a result, there remains an unmet clinical need for an unsedated, less expensive, and more accessible technique that could supersede diagnostic EGD. In this grant, we will develop a replacement for diagnostic EGD that combines video endoscopy with cellular- resolution in vivo microscopy in a swallowable, tethered capsule. Once swallowed, the tethered capsule endoscopy-endomicroscopy (TEEM) device will acquire wide area white light and microscopic images of the esophagus, stomach, and duodenum. Because patients will be unsedated, the procedure can be performed by non-physician personnel in an outpatient setting, thereby improving patient tolerance, increasing efficiency, and lowering costs, resulting in better screening and treatment of this important source of mortality/morbidity. In Aim 1, we will develop the TEEM imaging system and capsule that will incorporate a new cross-sectional, 1-m- resolution imaging modality known as OCT, a controllable-stiffness and articulating tether that will facilitate navigation of the stomach, side-viewing white light image acquisition, forward-viewing video, and algorithms for registering OCT and endoscopy imaging data for offline review. In Aim 2, we will conduct a histopathologic correlative biopsy study to determine the accuracy of OCT for diagnosing the most common upper GI tract diseases. TEEM tolerance, inter/intra-observer variability, and test-retest reproducibility will then be tested in 55 patients to verify that this technology meets the clinical requirements for upper GI tract screening (Aim 3).